The first 2 authors contributed equally in this article.
Pathway sensitivity analysis for detecting pro-proliferation activities of oncogenes and tumor suppressors of epidermal growth factor receptor-extracellular signal-regulated protein kinase pathway at altered protein levels
Article first published online: 23 JUN 2009
Copyright © 2009 American Cancer Society
Volume 115, Issue 18, pages 4246–4263, 15 September 2009
How to Cite
Li, H., Ung, C. Y., Ma, X. H., Liu, X. H., Li, B. W., Low, B. C. and Chen, Y. Z. (2009), Pathway sensitivity analysis for detecting pro-proliferation activities of oncogenes and tumor suppressors of epidermal growth factor receptor-extracellular signal-regulated protein kinase pathway at altered protein levels. Cancer, 115: 4246–4263. doi: 10.1002/cncr.24485
- Issue published online: 4 SEP 2009
- Article first published online: 23 JUN 2009
- Manuscript Accepted: 9 FEB 2009
- Manuscript Revised: 12 JAN 2009
- Manuscript Received: 3 OCT 2008
- Academic Research Fund. Grant Number: R-148-000-081-112 of 101
- National University of Singapore
- epidermal growth factor receptor-extracellular signal-regulated protein kinase pathway;
- pathway simulation;
- biologic networks;
- system biology
Mathematic models and sensitivity analyses of biologic pathways have been used for exploring the dynamics and for detecting the key components of signaling pathways.
The authors previously developed a mathematic model of the epidermal growth factor receptor-extracellular signal-regulated protein kinase (EGFR-ERK) pathway using ordinary differential equations from existing EGFR-ERK pathway models. By using prolonged ERK activation as an indicator that may lead to cell proliferation under certain circumstances, in the current study, a pathway sensitivity analysis was performed to test its capability of detecting pro-proliferative activities through altered protein levels to examine the effects on ERK activation.
The analysis revealed that 12 of 20 oncoproteins and 4 of 5 tumor suppressors were detected, consistent with reported experimental works. Because pathway dynamics depend on many factors, some of which were not included in the current models, failure to detect all known oncogenes and tumor suppressors can be because of the failure to include relevant crosstalk to other pathway components.
Overall, the current results indicated that pathway sensitivity analysis is a useful approach for detecting and distinguishing pro-proliferation activities of oncoproteins and suppressed proliferative activities of tumor suppressors at altered protein levels at least in the EGFR-ERK model. Cancer 2009. © 2009 American Cancer Society.